Deletion of the thrombin receptor PAR4 reduces diet-induced liver damage

Fatty liver, one of the most common liver diseases, is often caused by excessive intake of high- calorie food. The course of the disease ranges from simple hepatic steatosis to an inflammatory reaction to liver fibrosis and cirrhosis. Both, patients with and without cirrhosis have an enhanced risk to develop a hepatocellular carcinoma.

For the study of liver disease progression under high-calorie diet, wt and Par4 knock-out mice were fed with western diet for up to 50 weeks.

In the longitudinal analysis of the progression of fatty liver disease wt mice show a significant increase the concentration of the serum parameter AST, ALT and LDH, especially after 16 and/or 26 weeks. After 30 weeks, there was a significant increase in RNA expression of TGFb1, 2, and 3 and increased collagen formation in liver tissue, accompanied by increased expression of various chemokines and the formation of so-called crown-like structures mainly from recruited macrophages. After 40 weeks of feeding, 25% and after 50 weeks of feeding, 60% of the animals developed macroscopically visible liver tumors. In comparison, the Par4 knock-out animals showed significantly reduced concentrations of AST, ALT, and LDH during the course of feeding, and fibrosis of the liver is significantly reduced. In addition, no PAR4 knock-out animal showed tumors after 50 weeks and only 1 animal had developed a tumor after 40 weeks of feeding.

In comparision to the wt mice, the depletion of Par4 appears to lead to a reduction in liver injury induced by a high-calorie diet.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022